Of Mice And Women

Back in the early 1970s when I was a young nurse at Cincinnati General Hospital I was rejected from participation in a clinical study because I was female. At that time, the Hospital had a floor dedicated to clinical research, where patients or healthy subjects who were part of a clinical trial would often spend the night, as they were being monitored for efficacy or reactions after being given a dose of a test drug.

There were often sleep studies conducted where a person would be hooked up to electrodes and their cycles would be recorded to be compared to their perception of how they slept after being given a medication or a placebo. Money was paid for participation. Being a young new nurse, I needed the extra cash. A paid sleep study would have been perfect for me, as I could and still can sleep anywhere.

The hospital policy then, stated that including women of childbearing age in clinical research was not ethical due to the unknown effects of a formula on a developing fetus. In response to not being allowed to participate, I wrote a protest letter to the director of the hospital’s research department stating that it was unreasonable to exclude women.

Not all young women were pregnant or going to be pregnant. Plus, you could be tested for pregnancy before participation. I went on to say that females would be using the medications or therapies and should therefore have the reassurance of knowing they were tested on their gender too with a safe outcome. While I believed strongly in my argument, I didn’t pursue this further.

I hadn’t thought about this in a while, until I read the New York Times May 14, 2014 article titled, Labs Are Told to Start Including a Neglected Variable: Females.  The article points to a new NIH (National Institute of Health) warning that gender bias in research must end. This means that despite the complexity of understanding gender differences, both male and female animals should be included when preclinical testing is conducted.

Testing on people mostly happens after animal studies have been completed to ensure that the therapy is safe to study on humans. However, because women respond differently to treatments then men do, you wouldn’t really have the robust data needed to ensure its safety for women if only male animals are used in studies.  Key is that gender specific hormone cycling that could alter how they each metabolize a medication. While males have far more variability in regards to traits and behaviors, the reality is that women experience more severe side effects from new treatments than men.

Many of these adverse events could have been identified and resolved in the laboratory if there had been testing on female animals too. For example, the Food and Drug Administration recently told women to half their dose of the sleeping pill Ambien. New studies show that women metabolize the active ingredient of the drug more slowly than men, which could result in more side effects if they don’t decrease the dosing.

In 1994, the FDA made changes in its policies to allow women to participate in early phases of clinical drug trials.  Along with this, “the FDA issued guidelines promoting greater study and better analysis of patient subgroups including drugs in the elderly, separate analysis of trial data for both genders, and pediatric studies as well as dose-response information.” If we are encouraging participation of men and women in clinical drug trials, the earlier research with animals of both genders can only improve safety and a better outcome during clinical testing.

How did it come about that women were excluded from clinical trials? An abstract published in the US National Library of Medicine NIH, titled: Historical background of clinical trials involving women and minorities, by McCarthy CR provides a historical perspective on the ethical and clinical complexities when women are part of clinical research. Regulations issued in 1975 provided protection for pregnant women in research. In 1977, the regulations were furthered to include potentially pregnant women.

So, there you have it. On one level we sought to protect women from the unknown of clinical research and yet we desired to know that the medicines we were taking were safe for pregnant or possibly pregnant women. On another level, not all women were going to get pregnant for various reasons, yet there was still the potential for adverse reactions for every women. Adverse reactions can cause unwanted suffering, medical issues, increased health care costs and, in the worst case, death.

Why not include female and male animals in the preclinical drug testing? One reason for the lack of animal gender diversity includes the expense of ensuring that hormone variability in female animals isn’t going to confound the results. But, isn’t that the point, to find out what hormone cycling does to the therapeutic action of the therapy?

Most scientists would say: Of course! We know that women respond differently to a broad range of therapies and we need to learn more about why. However, cost factors in to this. Furthering this knowledge is expensive and takes time. When the funding just isn’t available, conclusions are made based on previous research done with male animals, which can be robust in many ways but limited in regards to gender diversity.

As a very sad example, had Thalidomide, a sedative, prescribed to pregnant women in the late 1950s to treat nausea that resulted in severe birth defects in thousands of babies, been tested on pregnant animals, its impact on a developing fetus may have been discovered.

Ms. Rabin rightly notes in an abstract titled: Female Mice Liberated For Inclusion in Neuroscience and Biomedical Research; there are sex differences, be it male or female, and that the biological variability in one over the other should not necessitate exclusion.

And, I totally agree!! Hopefully, the cost of the extra analyses needed during animal studies to better understand sex differences, will result in the development of safer medications for both women and men.